Microcapsules containing ultraviolet screening agent

Abstract

The invention relates to microcapsules, the core of which is wrapped by a gel shell, the core further comprising at least one active agent, and the shell comprising dispersed colloidal particles of UV-screening agent, to a method for the production of said microcapsules and to the use thereof in various fields of application.

Description

[0001] The present invention relates to a microcapsule whose liquid core is in the form of an aqueous, oily or oil-in-water (O / W) and water-in-oil (W / O) emulsion and is surrounded by a gel shell, the core also comprising at least one active agent, and the shell comprising dispersed colloidal particles of a UV-screening agent, and furthermore, to a method for producing the microcapsule and its use in various application fields, such as crop and / or seed treatment, human and / or animal nutrition, cosmetics and pharmaceuticals, soil and wastewater purification.

[0002] When reactive compounds, especially organic compounds, are exposed to ultraviolet (UV) light, they form free radicals through oxidation reactions. In organic molecules, mutations occur in the DNA bases that make up the genome that can be harmful to microorganisms.

[0003] The solar radiation energy reaching the ground is divided into the following parts: 5% ultraviolet radiation, 45% visible light radiation and 50% infrared radiation. Ultraviolet rays have proven to be the most destructive because they have greater energy.

[0004] The present invention relates to the use of a concentrated suspension of colloidal particles of a UV screener in a capsule shell to protect the active agent inside the capsule. In the case of microorganisms, the inventors have found that such incorporation improves their ability to survive exposure to UV radiation.

[0005] UV screeners are molecules or particles that absorb, reflect and / or scatter UV rays. They are often used in cosmetics in the form of nanoparticles to protect the skin from the harmful effects of UV rays.

[0006] The effectiveness of UV screeners depends on their ability to absorb, reflect and / or scatter light. Certain physicochemical parameters also influence these physical phenomena, such as particle size, refractive index and concentration.

[0007] The present invention therefore relates to a microcapsule having a liquid core surrounded by a gel shell, wherein the average diameter of the microcapsules when in hydrated form is between 50 and 4000 μm, and wherein:

[0008] a. The core further comprises at least one active agent, and

[0009] b. The shell comprises dispersed colloidal particles of a UV-screening agent, wherein the UV-screening agent is not a soluble antioxidant compound.

[0010] The present invention also relates to a method for producing microcapsules, comprising the following steps:

[0011] a. A first liquid solution containing at least one active agent is delivered separately in a double-layer wrapper, and a second liquid solution comprising colloidal particles of a biopolymer having gelling properties and dispersed UV shielding agent;

[0012] b. forming a series of droplets at the outlet of the double-layer wrapper, each droplet containing a central core formed by the first solution and a peripheral membrane formed by the second solution and completely covering the central core;

[0013] c. immersing each droplet in a gelling solution capable of reacting with a biopolymer having gelling properties, so that it changes from a liquid state to a gelling state and forms a gelling wrap, with the central core forming a liquid core;

[0014] d. Collect the formed capsules.

[0015] The invention also relates to microcapsules obtained by this production process.

[0016] The present invention relates to any use of microcapsules intended to protect active agents from the harmful effects of ultraviolet radiation, for example, when the capsules are stored under extreme light conditions, when the steps involved in the production process require exposure to ultraviolet light, or when it is used in various fields such as agriculture, agri-food, cosmetics or pharmaceuticals.

[0017] The invention relates to the use of microcapsules for treating plant crops and / or their seeds, for animal nutrition and / or feed, for human nutrition and / or food, for formulating cosmetic and / or pharmaceutical compositions and for purifying soil and wastewater.

[0018] The present invention also relates to a pharmaceutical composition comprising the microcapsules of the present invention.

[0019] The present invention also relates to a method for treating crops and / or their seeds, comprising broadcasting, foliar spraying or seed coating with the microcapsule suspension of the present invention.

[0020] Detailed description of the invention

[0021] Microcapsules

[0022] The term "microcapsule" herein refers to a capsule having an average diameter of less than 10 mm and comprising at least a core and a shell. Preferably, such capsules have a liquid core which is encapsulated by a nearly solid gel wrapper. Such capsules are used in many technical fields. The shell comprises one or more concentric or non-concentric compartments. Preferably, the microcapsule according to the present invention comprises only one core wrapped by a shell.

[0023] Therefore, these microcapsules are very different from microspheres, as microspheres are primarily composed of a solid or gel matrix containing multiple small inclusions.

[0024] Using microcapsules instead of microspheres allows microorganisms to move freely within a certain range.

[0025] According to a preferred embodiment of the present invention, the ratio of the core volume of the microcapsule to the total volume of the microcapsule is greater than 20%. Therefore, for a given volume of the shell, these microcapsules can protect a large volume of the core, thereby protecting the active agent.

[0026] Microcapsules are well known to those skilled in the art and can be made by different techniques and with shells having different compositions.

[0027] Typically, the microcapsules used in the present invention are produced according to the manufacturing method described in French Patent No. 2939012.

[0028] As described below, the microcapsules of the present invention may be in a dehydrated form. However, when they are in a hydrated form, such as suspended in an aqueous solution, the average diameter of the microcapsules of the present invention is between 50 and 4000 μm, preferably between 100 and 2000 μm, more specifically between 200 and 1000 μm, advantageously between 200 and 600 μm. The average diameter can be measured by various techniques well known to those skilled in the art, such as particle size determination based on laser diffraction, sieving separation or optical microscopy imaging.

[0029] In one embodiment, the microcapsules of the present invention further comprise an intermediate layer between the core and the shell. Preferably, this layer is composed of at least one biopolymer in solution or hydrogel form. Among other things, it will limit any interaction between the UV screening agent and the active agent.

[0030] Preferably, the microcapsules of the invention are free, that is, they are not contained in other structures such as membranes, spheres, gels or secondary encapsulations, but are in direct contact with the surrounding medium, typically a liquid (for example if they are in suspension) or a gas.

[0031] core

[0032] The core of the microcapsule contained in the present invention is a liquid core containing at least one active agent. Preferably, the viscosity of the core is less than 2000 mPa.s.

[0033] The core of the microcapsule of the present invention may be in the form of an aqueous, oily, or oil-in-water (O / W) or water-in-oil (O / W) emulsion.

[0034] "Aqueous core" refers to a core based primarily on an aqueous phase, in which the active agent is dispersed or dissolved.

[0035] "Oily core" refers to a core based predominantly on an oil phase, in which the active agent is dispersed or dissolved.

[0036] If the core is an oil-in-water (O / W) emulsion, the hydrophobic active agent will be dispersed in the oil droplets. This type of emulsion can also encapsulate both hydrophobic and hydrophilic active agents.

[0037] "Active agent" refers to an active substance, active molecule or active ingredient that is known and / or used for a specific purpose. Preferably, the active agent is sensitive to ultraviolet light, that is, exposure to ultraviolet light causes irreversible changes in the active agent, thereby reducing its activity.

[0038] Advantageously, the active agent is selected from microorganisms, natural extracts, semiochemicals and mixtures thereof.

[0039] "Microorganisms" refer to organisms that are invisible to the naked eye and can only be seen through a microscope, especially bacteria, fungi, microalgae and viruses.

[0040] "Natural extracts" refer to extracts of animal, vegetable or mineral origin, such as extracts of plants, algae, minerals and microorganisms, such as essential oils, etc.

[0041] For example, in one embodiment, the active agent is a biocontrol agent, a biofertilizer, and / or a biostimulant.

[0042] "Biological control agents" are agents that protect crops and / or their seeds from diseases or pests based on the use of natural mechanisms. These agents include macroorganisms (insects and nematodes), plant protection products consisting of microorganisms (viruses, bacteria and fungi), chemical mediators (pheromones and kairomones) and natural substances of plant, animal or mineral origin.

[0043] "Biofertilizer" refers to non-pathogenic substances or microorganisms that can increase the efficiency of plant nutrient utilization.

[0044] “Biostimulant” refers to non-pathogenic substances or microorganisms that stimulate natural processes to improve / benefit nutrient uptake, nutrient efficiency, abiotic stress tolerance and / or crop quality, regardless of the nutritional content of the biostimulant.

[0045] In another embodiment, the active agent can be a macronutrient (carbohydrate, fat and protein) or a micronutrient (vitamin, mineral, trace element or amino acid), preferably with organoleptic or nutritional properties. Thus, the active agent can be a dietary supplement, an agent that promotes digestion and / or absorption of certain compounds. For example, the active agent in the microcapsule of the present invention can be: vitamin, amino acid or fatty acid.

[0046] In another embodiment, the active agent can be a cosmetic. A cosmetic is any substance or mixture intended to come into contact with the surface of the human body (epidermis, hair and capillary system, nails, lips and external genitalia) or the teeth and oral mucosa, the sole or primary purpose of which is to cleanse, perfume, alter the appearance, protect, maintain good condition or correct body odor.

[0047] In another embodiment, the active agent may be an active ingredient in a pharmaceutical composition having a therapeutic or prophylactic effect.

[0048] In another embodiment, the active agent may be an active ingredient used to purify water or soil, such as in a wastewater treatment plant.

[0049] Preferably, the core of the capsule of the present invention does not contain UV-screening agent particles.

[0050] shell

[0051] Preferably, the microcapsule of the present invention comprises at least one liquid core, which is encapsulated by a nearly solid gel wrapper (called a "shell").

[0052] Preferably, the shell of the microcapsule of the present invention is mainly composed of a biopolymer with gelling properties, which accounts for a large proportion of the shell and is hereinafter referred to as the "main biopolymer". For example, the biopolymer with gelling properties can be alginate, gellan gum, xanthan gum, pectin, chitosan, agar or carrageenan.

[0053] Preferably, the material constituting the shell is biodegradable and bio-based. Preferably, the shell is semi-permeable to low molecular weight gases and molecules.

[0054] The gel forming the shell may be formed using physical or chemical processes, ie by coacervation or polymerization.

[0055] The gelation of these biopolymers can be achieved by temperature changes (gellan gum), pH changes (chitosan, pectin), or ionic changes (alginate, carrageenan).

[0056] Preferably, the shell of the microcapsule of the present invention is mainly composed of a biopolymer that obtains gel properties through ion or temperature changes.

[0057] Preferably, the shell of the microcapsule of the present invention is mainly composed of alginate.

[0058] The shell may also include one or more biopolymers in addition to the primary biopolymer, such as starch (in various forms, such as amylose, pregelatinized starch), potato protein, or another biopolymer having gelling properties in addition to the primary biopolymer, such as alginate, gellan gum, xanthan gum, pectin, chitosan, agar, or carrageenan.

[0059] Preferably, the shell of the microcapsules of the present invention comprises a gel containing water, one or more biopolymers having gelling properties, and a surfactant which may result from the method of its manufacture.

[0060] Preferably, the shell of the microcapsules of the present invention comprises a gel containing water and alkaline alginate and possibly a surfactant resulting from the method of its manufacture.

[0061] Preferably, the alkaline alginate is sodium alginate or potassium alginate. Alginates are produced by brown algae, the latter being known as Laminaria japonica, the English term "sea weed". The α-L-guluronic acid content of such alginates is advantageously greater than about 50%, preferably greater than 55% or even greater than 60%.

[0062] Advantageously, the surfactant is an anionic surfactant, a nonionic surfactant, a cationic surfactant or a mixture thereof.The molecular weight of the surfactant is between 150 g / mol and 10,000 g / mol, advantageously between 250 g / mol and 1500 g / mol.

[0063] In the case where the surfactant is an anionic surfactant, for example, it is selected from alkyl sulfates, alkyl sulfonates, alkyl aryl sulfonates, alkyl phosphates, dialkyl sulfosuccinates, alkaline earth salts of saturated or unsaturated fatty acids. Advantageously, these surfactants have at least one hydrophobic hydrocarbon chain with a carbon number greater than 5 or even 10 and at least one anionic hydrophilic group, such as sulfate, sulfonate or carboxylate connected to one end of the hydrophobic chain. In the case where the surfactant is a cationic surfactant, for example, it is selected from alkyl pyridine or alkyl ammonium halide salts, such as n-ethyl dodecyl ammonium chloride or ammonium bromide or hexadecyl ammonium chloride and ammonium bromide (CTAB). Advantageously, these surfactants have at least one hydrophobic hydrocarbon chain with a carbon number greater than 5 or even 10 and at least one cationic hydrophilic group, such as quaternary ammonium cations. In the case where the surfactant is a nonionic surfactant, for example, it is selected from polyoxyethylene and / or polyoxypropylene derivatives of fatty alcohols, fatty acids or alkylphenols, arylphenols, or selected from alkyl glucoside, polysorbate and coconut amide.

[0064] In one embodiment, the surfactant is sodium lauryl sulfate (SLS, also known as sodium cocoyl sulfate) and / or polyoxyethylene sorbitan monoester (polysorbate 80).

[0065] Preferably, the surfactant is polyoxyethylene sorbitan monoester (polysorbate 80).

[0066] In one embodiment, the mass content of the surfactant in the shell is greater than 0.001%, advantageously greater than 0.1%. Advantageously, the mass concentration of the surfactant is about 0.03%.

[0067] The shell thickness of the microcapsules is preferably between 0.1% and 30%, advantageously between 1% and 20%, more particularly between 10% and 20%, of the capsule diameter.

[0068] The shell of the microcapsule also contains dispersed UV screener colloidal particles. In fact, preferably, the UV screener particles are located in the shell of the microcapsule, and advantageously, not in the core of the microcapsule. This allows the use of less screener to obtain an equivalent UV protection effect, while also limiting the interaction between the UV screener and the active agent.

[0069] "UV screening agent colloidal particles" refer to particles with an average size between 10nm and 10μm, preferably between 100nm and 5μm. Generally speaking, the smaller the particles, the more effective they are in resisting UV rays. These screening agents can also be used to cover microcapsules.

[0070] Preferably, the UV screener is not a soluble antioxidant compound. In fact, these compounds tend to degrade more rapidly once exposed to UV light.

[0071] The ultraviolet shielding agent of the present invention may be organic or inorganic, or a mixture of organic and inorganic shielding agents.

[0072] Preferably, the UV shielding agent is selected from titanium oxide, carbon black, biochar, latex, silica, clay and mixtures thereof.

[0073] Biochar is a product of biomass pyrolysis and is used as an agricultural soil conditioner.

[0074] The clays used as UV screeners are talc or kaolin and mixtures thereof.

[0075] Kaolin is a type of clay used to filter ultraviolet light. It is also used to protect certain crops from agricultural pests and diseases.

[0076] Preferably, the UV screening agent of the present invention is biodegradable and / or edible and / or cosmetically and / or pharmaceutically acceptable.

[0077] "Cosmetically acceptable" herein means that these compositions and molecular entities do not produce side effects, allergies or other adverse reactions when administered to a subject. Thus, cosmetically acceptable UV screeners are compatible with the skin, epidermis and / or mucous membranes and do not cause discomfort or, more generally, conditions that may cause the user to suspend or stop using the cosmetic composition containing it.

[0078] Herein, "pharmaceutically acceptable" means that these compositions and molecular entities will not or rarely produce side effects, allergies or other adverse reactions when administered to a subject. Therefore, pharmaceutically acceptable UV screeners will not cause situations that may cause users to suspend or stop using the pharmaceutical composition containing it.

[0079] "Dispersed UV screener particles" are particles dispersed in the microcapsule shell in order to produce a uniform UV protection effect on the surface of the microcapsule.

[0080] The microcapsules of the present invention may be in a dehydrated form. Preferably, the dehydration is local and the moisture content of the microcapsules of the present invention is less than 10%, measured by a moisture analyzer after dehydration.

[0081] In the dehydrated form, the average diameter of the microcapsules tends to decrease. Preferably, the average diameter of the microcapsules of the present invention in the dehydrated form is from 10 μm to 4 mm.

[0082] Production method

[0083] The present invention also relates to a method for producing microcapsules, comprising the following steps:

[0084] delivering a first liquid solution containing at least one active agent and a second liquid solution containing colloidal particles of a biopolymer having gelling properties and dispersed UV-screening agents separately in the double-layer wrap;

[0085] A series of droplets are formed at the outlet of the double-layer wrapper, each droplet containing a central core formed by the first solution and a peripheral membrane formed by the second solution and completely covering the central core;

[0086] Each droplet is immersed in a gelling solution that can react with a biopolymer having gelling properties, so that it changes from a liquid state to a gelling state and forms a gelling wrap, with the central core forming a liquid core;

[0087] The formed capsules were collected.

[0088] Preferably, the present invention relates to a method for producing microcapsules, comprising the following steps:

[0089] delivering a first liquid solution containing at least one active agent and a second liquid solution containing alkaline alginate and dispersed colloidal particles of a UV-screening agent separately in the double-layered wrap;

[0090] A series of droplets are formed at the outlet of the double-layer wrapper, each droplet containing a central core formed by the first solution and a peripheral membrane formed by the second solution and completely covering the central core;

[0091] immersing each droplet in a gelling solution containing a reagent capable of reacting with alkaline alginate to change it from a liquid state to a gelling state and form a gelling wrap, with the central core forming a liquid core;

[0092] The formed capsules were collected.

[0093] The definitions in the section on microcapsules also apply here.

[0094] In one embodiment of the production method of the present invention, the second solution contains at least one surfactant before contacting with the first solution.

[0095] Preferably, the surfactant is selected from anionic surfactants, cationic surfactants and nonionic surfactants or mixtures thereof.

[0096] For example, the surfactant is an alkyl sulfate, an alkyl sulfonate, an alkyl aryl sulfonate, an alkyl phosphate, a dialkyl sulfosuccinate, an alkaline earth salt of a saturated or unsaturated fatty acid, an alkyl pyridine or an alkyl ammonium halide salt, such as n-ethyldodecyl ammonium chloride or ammonium bromide or hexadecyl ammonium chloride and ammonium bromide, a polyoxyethylene and / or polyoxypropylene derivative of a fatty alcohol, a fatty acid or an alkylphenol, or is selected from aromatic phenols, alkyl glucosides, polysorbates, coconut amide or mixtures thereof.

[0097] In one embodiment, the surfactant is sodium lauryl sulfate (SLS, also known as sodium cocoyl sulfate) and / or polyoxyethylene sorbitan monoester (polysorbate 80).

[0098] Preferably, the surfactant is polyoxyethylene sorbitan monoester (polysorbate 80).

[0099] In the second solution, preferably, the total mass percentage of the surfactant is greater than 0.01%, and advantageously is between 0.01% and 0.5% (mass ratio).

[0100] Advantageously, in the second solution, the mass content of the biopolymer having gelling properties is less than 5% (mass ratio), preferably between 0.5% and 3% (mass ratio).

[0101] Preferably, if the microcapsules produced have a shell mainly containing alginate, the mass content of alkaline alginic acid in the second solution is advantageously less than 5% (mass ratio), and preferably between 0.5% and 3% (mass ratio).

[0102] Preferably, the content of α-L-guluronic acid in the alkaline alginate of the second solution is greater than 50%, or even greater than 55%.

[0103] Preferably, the second liquid solution contains 0.1% v / v to 20% v / v of the ultraviolet shielding agent.

[0104] After collecting the formed capsules, at the outlet of the double-layer wrap, the ratio of the flow rates of the first solution to the second solution is between 0.01 and 100, advantageously between 0.05 and 50, more specifically between 0.1 and 10, and the thickness of the gel wrap is between 0.1% and 30% of the capsule diameter, advantageously between 1% and 20%, more specifically between 10% and 20%.

[0105] The "gelling solution capable of reacting with the biopolymer" refers to a solution at a specific temperature or a specific pH, or containing a specific reactant that can transform the biopolymer of the second liquid solution from a liquid state to a gelled state.

[0106] If the microcapsules produced have a shell mainly containing alginate, the gelling solution is, for example, an aqueous solution of reactants of the XNLM type, wherein X is advantageously a halide ion, such as chloride, bromide, iodide or fluoride, I is advantageously a polyvalent cation of an alkaline earth metal, such as calcium, magnesium or barium, and n and m are greater than or equal to 1. Preferably, the gelling solution also comprises a surfactant, such as polysorbate 20 or polysorbate 80.

[0107] When the second solution is in contact with the gelling solution, the multivalent ions present in the gelling solution thus formed are able to react with the alginate to form bonds between the different alginate chains present in the second solution. In the case where the alginate is sodium alginate (NaAlg) and the reactant is calcium chloride, the reaction that occurs is as follows:

[0108] 2NaAlg+CaCl 2 →Ca(Alg) 2 +2NaCl

[0109] In the production method of the present invention, preferably, the concentration of the reactants in the gel solution is between 5% and 20% (mass ratio).

[0110] Preferably, the gelling solution is arranged below and away from the outlet of the double-layer wrap, so that the droplets co-extruded in the double-layer wrap spontaneously fall into the gelling solution under the action of gravity through a certain amount of air, thereby being immersed therein.

[0111] In one embodiment, the formed microcapsules may be subjected to an additional washing step by entering a washing and storage solution consisting primarily of water.

[0112] The production method of the present invention may also include a microcapsule dehydration step (step e.). This step may be performed by techniques well known to those skilled in the art, such as by thermal drying techniques or cold drying techniques. Preferably, this step is performed by drying, freeze drying or osmotic dehydration. In a specific embodiment, the dehydration is performed by fluidized bed drying and / or freeze drying. Preferably, the dehydration step removes at least 90% by weight of the water from the microcapsules.

[0113] The present invention also relates to microcapsules obtained by the production method according to the present invention.

[0114] Uses and methods

[0115] The definitions in the section on microcapsules also apply here.

[0116] Preferably, in the methods and uses according to the invention, the microcapsules are used as such, that is, they are not contained in another structure (such as a film, pellet, gel or secondary encapsulation), but are used directly, possibly suspended in a liquid.

[0117] The present invention relates to the use of the microcapsules according to the invention for treating plants, plant crops and / or their seeds.

[0118] "Treatment of plant crops and / or their seeds" refers to biocontrol, biofertilization and / or biostimulation treatments which may be carried out before, during or after planting.

[0119] In fact, the active agent of the microcapsule of the present invention can be an agent that has an effect on plant crops and / or their seeds. Specifically, the active agent can protect the crops and / or their seeds from diseases or pests, and can also be used as a fertilizer and / or promote the growth of plant crops and / or their seeds.

[0120] Therefore, the present invention relates in particular to the use of microcapsules for treating plant crops and / or their seeds, wherein the active agent is a biocontrol agent, a biofertilizer and / or a biostimulant.The microcapsules can be used suspended in a liquid or in a dehydrated and solid form.

[0121] The present invention includes a method for treating crops and / or seeds, which is applied to the microcapsules of the present invention. Therefore, the present invention also relates to a method for treating crops and / or seeds, comprising broadcasting, foliar spraying or coating seeds with the microcapsules of the present invention, preferably, in the microcapsules of the present invention, the active agent is a biocontrol agent, a biofertilizer and / or a biostimulant. In this method, the microcapsules can be suspended in a liquid or used in a dehydrated and solid form.

[0122] In another embodiment, the present invention relates to the use of the microcapsules of the present invention for nutrition and / or food for animals and / or humans, preferably for non-therapeutic uses. In this embodiment, preferably, the active agents used are not therapeutic active agents, i.e., they have nutritional or food value, but cannot prevent or treat diseases in the consumer. Preferably, the active agents used are edible agents, preferably edible agents with organoleptic or nutritional properties. Therefore, in this use, active agents with nutritional or food value, but cannot prevent or treat diseases in the consumer are preferred.

[0123] "Food" refers to food that is habitually or frequently ingested. In fact, the microcapsules can contain various active agents that can improve the properties of the food, such as its organoleptic properties, shelf life or bioavailability.

[0124] "Nutrition" refers to the intake of dietary supplements during treatment or more often on time to avoid or compensate for the lack of essential nutrients. In fact, the microcapsules of the present invention can contain various active agents that improve nutrient intake or modify the intestinal flora by increasing their bioavailability.

[0125] "Animal" refers to wild or domesticated animals. Preferably, the animal is a domesticated, farmed animal or a pet. Specifically, the animal involved in the present invention is selected from pets, such as dogs, cats, fish, rabbits, horses, turtles, and farmed species, such as cattle (cows, bulls), sheep (sheep), goats, rabbits, pigs (boars), camels and birds raised in poultry farming (chickens, quails, etc.).

[0126] The invention also relates to the use of the microcapsules according to the invention for formulating cosmetics. In this embodiment, preferably, the active agents used are not therapeutically active agents, ie they have cosmetic value but cannot prevent or treat diseases of the user.

[0127] The present invention also relates to the use of the microcapsules of the present invention in the formulation of pharmaceutical compositions. In this embodiment, the active agents used are preferably therapeutically active agents, ie they can prevent or treat diseases in the consumer.

[0128] In fact, the use of the microcapsules according to the invention makes it possible to facilitate the storage, packaging or preparation of cosmetic or pharmaceutical preparations while maintaining the good quality of the active agent.

[0129] Pharmaceutical synthesis and therapeutic applications

[0130] The present invention also relates to a pharmaceutical composition comprising the microcapsules of the present invention. The present application also relates to using the microcapsules of the present invention as a drug.

[0131] The present invention also relates to a method for treating a subject, comprising administering a therapeutically effective amount of the microcapsules of the present invention to a subject in need thereof.

[0132] In this embodiment, advantageously, the microcapsules of the present invention contain a therapeutically active agent.

[0133] "Therapeutically active agent" refers to an active agent as defined above in the microcapsule section, which is known and / or used for a specific therapeutic purpose, ie, known and / or used to treat or prevent a disease.

[0134] As used herein, the term "pharmaceutical composition" refers to a mixture or solution containing at least one therapeutic agent, which is intended for administration to a subject to prevent or treat a particular disease affecting the subject.

[0135] Therefore, preferably, the pharmaceutical composition herein also includes a pharmaceutically acceptable excipient.

[0136] "Pharmaceutically acceptable" herein means that these compounds and molecular entities do not cause side effects, allergies or other adverse reactions when administered to a subject.

[0137] The term "subject" herein refers to an organism, preferably a mammal, more specifically a human being.

[0138] The term "therapeutically effective amount" herein refers to an effective amount in the desired time period and dosage to achieve the desired therapeutic effect. The therapeutically effective amount may vary depending on factors such as the disease, the scope of the disease, the age, sex and weight of the subject, and the ability of the microcapsules to produce the desired therapeutic effect. The therapeutically effective amount includes an amount in which any toxic or harmful effects are offset by the beneficial therapeutic effects. The therapeutically effective amount also includes an amount sufficient to provide a benefit, such as a clinical benefit.

[0139] Preferably, the pharmaceutical composition is suitable for the route of administration.

[0140] In one embodiment, the pharmaceutical composition is suitable for oral, sublingual, buccal, intranasal or topical administration.

[0141] The present invention also relates to the use of the microcapsules of the present invention in the manufacture of drugs. The present invention also relates to the use of the microcapsules of the present invention in the preparation of pharmaceutical compositions.

[0142] For these uses, the microcapsules of the invention advantageously contain a therapeutically active agent.

[0143] In fact, the use of microcapsules according to the present invention can facilitate the storage, packaging or preparation of pharmaceutical compositions while retaining the active agent.

[0144] "Treatment" here means partially or substantially achieving one or more of the following results: partially or completely reducing the scope of the disease, improving clinical symptoms or indicators related to the disease, delaying, inhibiting or preventing the progression of the disease.

[0145] "Prevention" herein refers to partially or substantially achieving one or more of the following results: preventing or delaying the onset of a disease or at least one symptom, and preventing or delaying the deterioration of indicators related to the onset of the disease.

[0146] The invention also relates to the use of the microcapsules according to the invention for the purification of soil or wastewater. In fact, such a composition can protect the active agent from the effects of ultraviolet rays, for example when it is used in wastewater treatment plants or on soil surfaces.

[0147] In the specification and the following examples, unless otherwise indicated, percentages are percentages by weight, and numerical ranges are expressed in the format of "between ... and ...", "... to ..." or "greater than ..." (limits indicated).

[0148] Throughout the application, unless otherwise specified, "comprising a" or "including a" means "comprising at least one" or "including at least one".

[0149] The following examples present the field of the invention in an illustrative and non-limiting manner.

[0150] picture:

[0151] [Fig 1] Figure 1 : Changes in the survival percentage of Bacillus encapsulated with carbon black as a function of exposure time to artificial ultraviolet light.

[0152] [Fig 2] Figure 2 : Bacterial survival under UV exposure. These curves represent the survival of Paraburkholderia phytofirmans PSJN in suspension (dashed curve) and the survival of bacteria encapsulated in the microcapsules of the present invention, wherein biochar acts as a UV screener.

[0153] [Fig 3] Figure 3 : Comparison of the survival rates of phages encapsulated with biochar in shells and those not encapsulated with biochar and those in suspension, all exposed to artificial ultraviolet radiation. Example:

[0154] Embodiment 1:

[0155] Accelerated aging tests were performed on bacterial samples. The survival of Bacillus spores was exposed to artificial ultraviolet light both in suspension (unencapsulated) and in an encapsulated state. The bacteria were encapsulated in a shell formed by alginate and carbon black, which is a UV screener. The UV source used was an oven equipped with a mercury vapor lamp with a power of about 18 times the power of solar radiation (at noon in the summer in the United States). That is, one minute in the oven is equivalent to about 18 minutes outdoors. Two exposure times were tested: 3 minutes and 5 minutes.

[0156] The results are as follows Figure 1 The inventors have observed that the survival rate of bacteria in the encapsulated state is higher than that in the suspended state. After 5 minutes of exposure (equivalent to 1.5 hours outdoors), the survival rate of bacteria in the suspended state is 1%, while the survival rate of bacteria in the encapsulated state is 57%.

[0157] Embodiment 2:

[0158] Encapsulation operating conditions:

[0159] Core solution (or core fluid): Bacteria are suspended in TSB (Tryptone Soy Broth) medium diluted to 1 / 10 to limit bacterial proliferation during UV exposure.

[0160] Shell solution (or shell fluid): 1.8% (mass ratio) alginate solution, 0.5 mM SDS surfactant, 1.5% v / v biochar.

[0161] The flow rate ratio between the core and shell suspensions was set to 0.5. Therefore, the inventors wanted to maximize the shell thickness.

[0162] The total flow rate of the fluid was 340 mL / h.

[0163] Under these conditions, the capsules formed had an average diameter of 516 μm and a coefficient of variation (CV) of 17%.

[0164] Two UV screeners were selected for testing: biochar and kaolin clay.

[0165] The characteristics of the two screening agents were measured to verify their compatibility with the microencapsulation method. Therefore, the particle size distribution of their components was studied. In addition, the absorbance of these compounds to UV light was studied by spectrophotometry. The inventors observed that, for the same volume fraction (0.01%), kaolin had a slightly higher absorption of UV light than biochar.

[0166] The effectiveness of the biochar UV protection was evaluated by measuring the survival of bacteria encapsulated with biochar in shells, bacteria in suspension, and bacteria without biochar encapsulation, all exposed to artificial UV light. The bacteria used for these tests belonged to the species Paraburkholderia phytofirmans of the PSJN strain. These bacteria stimulate plant growth and help them resist certain biotic and abiotic insults.

[0167] The results obtained from these experiments are as follows Figure 2 The survival rate of bacteria encapsulated with 1.5% v / v biochar was higher than that of bacteria in suspension or bacteria not encapsulated with biochar. In fact, after 10 minutes of exposure, the survival rate of bacteria in suspension was 8%, while that of bacteria encapsulated with biochar was 46%.

[0168] Therefore, encapsulation with biochar in shells is a very effective solution to protect microorganisms from UV damage.

[0169] The performance of biochar in terms of protection against UV radiation was also evaluated against bacteriophages of strain M13K07. Two capsule prototypes were produced and their performance was evaluated. Prototypes 1 and 2 corresponded to wet alginate capsules without and with biochar, respectively.

[0170] The encapsulation operation conditions are as follows:

[0171] The nozzle diameter was 200 μm. The total flow rate of the core and shell fluids (ie, Qtot) was 500 ml / h, the flow rate ratio between the core and shell fluids (ie, Rq) was 0.8, and the film thickness was at least 30 μm.

[0172] Core solution (or core fluid): Phages are suspended in a physiological medium diluted to 1 / 200 to limit bacterial proliferation during UV exposure.

[0173] Shell solution (or shell fluid): 1.8% (mass ratio) alginate solution, 0.5 mM SDS surfactant, 2.9% v / v biochar.

[0174] Under these conditions, the mean diameter of prototype capsule 1 was 462 μm with a coefficient of variation (CV) of 17%.

[0175] The average diameter of prototype capsule 2 was 542 μm and the coefficient of variation (CV) was 18%.

[0176] The survival of phages encapsulated with biochar in shells, phages not encapsulated with biochar and phages in suspension were evaluated when exposed to artificial UV radiation. The results obtained from these experiments are shown in Figure 2. Figure 3 As shown in Table 1 below.

[0177] [Tab 1] Table 1

[0178]

[0179] After 30 minutes, the survival of phage in suspension was 0.00005% (i.e., approximately 6 log loss), when biochar was present in the shell, the survival of phage in encapsulated form was 30% (i.e., 0.5 log loss), and when biochar was present in the shell, the survival of phage in encapsulated form was 0.002% (i.e., approximately 4 log loss).

[0180] These results confirm that microorganisms in encapsulated form (here, phages) are effectively protected from UV rays when biochar is present in the shell. In addition, slightly higher survival rates were observed when the phages were encapsulated than when they were suspended.

[0181] Embodiment 3:

[0182] Encapsulation operating conditions:

[0183] Core solution (or core fluid): an inverse emulsion (O / W – water in oil) containing phenylalanine dissolved in the aqueous phase. The emulsion was prepared as follows:

[0184] Phenylalanine (960 mg) was dissolved in 120 ml of ultrapure water with a magnetic bar for 30 minutes. 1.37 g of polyglycerol ricinoleate (PGPR90) surfactant was added to the MCT oil. PGPR 90 was dispersed in the oil phase using a stirrer at a speed of 12,000 rpm for 2 minutes. The water phase was then added to the oil phase under stirring by the stirrer to form an emulsion. During the addition of the water phase to the oil phase, the stirrer speed was 18,000 rpm.

[0185] Shell solution (or shell fluid): 1.8% (mass ratio) alginate solution, 0.5 mM SDS surfactant, 4% (mass ratio) E-153 charcoal.

[0186] The flow rate ratio between the core solution and the shell emulsion was set to 0.5.

[0187] The total flow rate of the fluid was 350 mL / h.

[0188] The nozzle diameter is 145 μm.

[0189] UV irradiation was performed using a lamp with a wavelength of 254 nm and an irradiance of 0.76 mW / cm2. The sample was placed 10 cm away from the irradiation source. The UV protection effect of the activated carbon was evaluated by spectrophotometry by measuring the absorbance of the aqueous phase of the emulsion at 280 nm at exposure times t0, t20 min, and t1 h for the emulsion alone, the emulsion without charcoal encapsulation, and the emulsion encapsulated with charcoal, respectively.

[0190] 500 mg to 1 g of sample was added to a 15 ml test tube containing 8 ml of PBS and 25 mM EDTA, and the test tube was placed on a stirrer for 20 minutes to extract the aqueous phase of the emulsion. The test tube was then placed in an ultrasonic bath for 8 minutes. Finally, the test tube was placed in a centrifuge at 4700 rpm for 15 minutes. The aqueous phase below the oil phase of each test tube was then collected and filtered using a filter with a porosity of 0.2 μm.

[0191] result:

[0192] Phenylalanine exposed to this UV source is modified and its absorbance at 280 nm increases with exposure time. The lower this absorbance increase, the more effective the UV protection.

[0193] After 1 hour, the absorbance at 280 nm of the emulsion sample alone increased by more than 300-fold. For the emulsion without charcoal encapsulation, the absorbance increased by 13-fold, while for the charcoal-containing capsules, the absorbance was limited to less than 2-fold.

[0194] Table 2: Absorbance of the aqueous phase of the emulsion at 280 nm at exposure times t0, t20 min and t1h

[0195]

[0196] Table 3: Increase in absorbance at 280 nm of the aqueous phase of the emulsions after exposure to UV light for 20 minutes and 1 hour

[0197] Emulsion Emulsion without charcoal encapsulation Emulsion encapsulated with charcoal 20 minutes 9360％ 502％ 10％ 1 hour 33357％ 1222％ 98％

Claims

1. The microcapsule has a liquid core surrounded by a gel shell, characterized in that: When the microcapsules are in hydrated form, the average diameter of the microcapsules is between 50 and 4000 μm and is characterized by: a. The core further comprises at least one active agent, and b. The shell comprises dispersed colloidal particles of a UV-screening agent, wherein the UV-screening agent is not a soluble antioxidant compound.

2. The microcapsule according to claim 1, characterized in that The core contains particles of UV screener.

3. The microcapsule according to claim 1 or 2, comprising an intermediate layer between the core and the shell.

4. The microcapsule according to any one of claims 1 to 3, characterized in that UV screeners are either organic or inorganic.

5. The microcapsule according to any one of claims 1 to 4, characterized in that The UV shielding agent is selected from the group consisting of titanium oxide, carbon black, biochar, latex, silica, clay, and mixtures thereof.

6. The microcapsule according to any one of claims 1 to 5, characterized in that The active agent is selected from the group consisting of microorganisms, natural extracts, semiochemicals and mixtures thereof.

7. The microcapsule according to any one of claims 1 to 6 is present in a dehydrated form.

8. The production method of microcapsules comprises the following steps: a. A first liquid solution containing at least one active agent is delivered separately in a double-layer wrapper, and a second liquid solution comprising colloidal particles of a biopolymer having gelling properties and dispersed UV shielding agent; b. forming a series of droplets at the outlet of the double-layer wrapper, each droplet containing a central core formed by the first solution and a peripheral membrane formed by the second solution and completely covering the central core; c. immersing each droplet in a gelling solution capable of reacting with a biopolymer having gelling properties, so that it changes from a liquid state to a gelling state and forms a gelling wrap, with the central core forming a liquid core; d. Collect the formed capsules.

9. The method for producing microcapsules according to claim 8, characterized in that: The second liquid solution contains 0.1 to 20% v / v of an ultraviolet light shielding agent.

10. The method for producing microcapsules according to claim 8 or 9, comprising a step of dehydrating the microcapsules (step e.).

11. Microcapsules obtainable by the production method according to any one of claims 8 to 10.

12. Use of the microcapsules according to any one of claims 1 to 7 and 11 for treating plant crops and / or their seeds.

13. A method for treating crops and / or their seeds comprising broadcasting, foliar spraying or seed coating with a microcapsule suspension according to any one of claims 1 to 7 and 11.

14. Use of the microcapsules according to any one of claims 1 to 7 and 11 in animal nutrition and / or feed.

15. Use of the microcapsules according to any one of claims 1 to 7 and 11 for human nutrition and / or food.

16. Use of the microcapsules according to any one of claims 1 to 7 and 11 for formulating cosmetics 17. Use of the microcapsules according to any one of claims 1 to 7 and 11 for formulating a pharmaceutical composition.

18. A pharmaceutical composition comprising the microcapsules according to any one of claims 1 to 7 and 11.

19. Use of the microcapsule according to any one of claims 1 to 7 and 11 for purifying soil or wastewater.

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